Project Summary/Abstract This is the third competitive renewal of this grant application that was funded for the past 15 years. Over the years funding through this grant application led to several milestone observations and new discoveries, which include: The first description of Akt1-/- mice and the first genetic evidence that Akt is required for cell survival. Showing that Inhibition of early apoptotic events by Akt is dependent on the first committed step of glycolysis and mitochondrial hexokinase. The first phenotypic description of Akt1/2 DKO mice, and the first genetic proof that Akt is required for mTORC1 activation. Hexokinase- mitochondria interaction is required for Akt mediated cell survival. The first evidence that the deficiency of Akt1 is sufficient to suppress tumor development in Pten+/- mice. The first evidence that Akt1-/- mice are resistant to mammary gland and skin tumorigenesis, and that Akt exerts its pro-proliferative effect through mTORC1 activation. Finding the Achilles' heel of Akt, and that Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Finding that leptin deficiency is the underlying mechanism for Akt deficiency induced diabetes that can be cured by leptin administration. Employing for the first time sysytmic Akt1 deletion in adult mice to show that it could regress tumors after tumor onset. Systemic deletion of Akt1 and Akt2 in adult mice elicit rapid mortality and heaptic deletion of Akt1 and Akt2 surpsingly induces hepatocellular carcinoma (HCC). These recent findings manifest the importance of studying the function of the indvidual Akt isoforms not only in vitro in tissue culture, but also in a whole organsim epscially with respect to cancer therapy. In the first part of this renewal application we will follow mechansically our recent unexpected results. In the second part of this application, we will detremine the consequnces of deleting individuall Akt isoforms systemically and in a cell autonmous manner on breast cancer development and metastasis. Finally, we will exploit the role of Akt in metabolism to selectively eradicate cancer cells displaying hyperactive Akt in mouse models of prostate cancer.